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Preparation of cyclic imides from alkene-tethered amides: application of homogeneous Cu(II) Cite this: RSC Adv., 2020, 10, 7698 catalytic systems†
Zhenghui Liu, *a Peng Wang,bc Hualin Ou,b Zhenzhong Yan,a Suqing Chen,a Xingxing Tan,bd Dongkun Yu,d Xinhui Zhaod and Tiancheng Mu *d
A Cu-based homogeneous catalytic system was proposed for the preparation of imides from alkene- Received 11th December 2019 tethered amides. Here, O acted as a terminal oxidant and a cheap and easily available oxygen source. Accepted 5th February 2020 2 The cleavage of C]C bonds and the formation of C–N bonds were catalyzed by Cu(II) salts with proper DOI: 10.1039/c9ra10422d nitrogen-containing ligands under 100 C. The synthesis approach has potential applications in rsc.li/rsc-advances pharmaceutical syntheses. Moreover, scaled-up experiments confirmed the practical applicability.
found to be able to achieve such preparations. In 2016, Shimizu Creative Commons Attribution 3.0 Unported Licence. 1. Introduction et al. completed the direct synthesis of cyclic imides by using
Cyclic imides are becoming increasingly popular in the phar- carboxylic anhydrides and amines using Nb2O5 as a water- maceutical eld.1–5 Some drug molecules bearing cyclic imide tolerant Lewis acid catalyst without solvents (Scheme 2c).12 In structures are shown in Scheme 1. Among them, lenalidomide, 2017, Gaunt et al. set up a Co-catalyzed carbonylative cyclization carmofur, uorouracil, and aminoglutethimide are antineo- procedure of unactivated, aliphatic C–H bonds with a combination 13 plastic drugs; utamide is an antiu drug; and phensuximide, of Co(acac)2, PhCOONa, Ag2CO3, PhCl, and CO (Scheme 2d). phenytoin, and glutethimide are antiepileptic, antiarrhythmic, In addition, other methods such as electrocatalysis and and sedative-hypnotic drugs, respectively. The preparations of photocatalysis could also be used in this transformation 14,15 This article is licensed under a imides and cyclic imides have been paid much attention over (Scheme 2e and f). the years.6–9 As shown in Scheme 2, certain methods were The valid and selective oxidation of organic compounds gradually proposed. In 2005, Higuchi et al. proposed an oxida- offers the opportunity for the streamlined conversion of simple tion method of amides with 2,6-dichloropyridine N-oxide cata- precursors into value-added products.16 Oxidation reactions, Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. lyzed by ruthenium porphyrin in benzene at a low temperature together with polymerizations and carbonylations, constitute of 40 C overnight (Scheme 2a).10 Aer that, more nonnoble the largest industrial applications in the eld of homogeneous metals were employed in this type of transformation. In 2009, catalysis, and substantial value-added bulk and ne chemicals Beller et al. translated hex-3-yne into cyclic imides with CO and can be fabricated through this technology.17 With the superi- ffi NH3 catalyzed by [Fe3(CO)12] in THF at 120 C for 16 h, which ority of environmental compatibility, low cost, and high e - was the rst report on the iron-catalyzed synthesis of succini- ciency, O2 is becoming a frequently used oxidant in both mides via the carbonylation of diverse internal and terminal experimental and industrial scenarios.18,19 With regard to green alkynes with amines or ammonia to achieve good selectivity and high activity (Scheme 2b).11 Later, metallic oxides were also
aSchool of Pharmaceutical and Materials Engineering, Taizhou University, Taizhou 318000, Zhejiang, China. E-mail: [email protected] bBeijing National Laboratory for Molecular Sciences, CAS Research/Education Center for Excellence in Molecular Sciences, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China cKey Laboratory of Green Chemical Media and Reactions, Ministry of Education, School of Chemistry and Chemical Engineering, Henan Normal University, Xinxiang 453007, Henan, China dDepartment of Chemistry, Renmin University of China, Beijing 100872, China. E-mail: [email protected] † Electronic supplementary information (ESI) available: Tables S1–S15, Scheme S1, ESI-MS measurement, NMR spectra of substrates, products and intermediate. See DOI: 10.1039/c9ra10422d Scheme 1 Pharmaceutical molecules with cyclic imide structures.
7698 | RSC Adv.,2020,10, 7698–7707 This journal is © The Royal Society of Chemistry 2020 View Article Online Paper RSC Advances
employed in the oxidation of alkene-tethered amide 1a into cyclic imide 2a in MeCN at 100 CinanO2 environment under
atmospheric pressure. Cu(acac)2 with ligand A (neocuproine) exhibited outstanding catalytic performance with the highest 2a yield of 85%, while the others behaved moderately or even badly under otherwise identical conditions. Phosphine ligands were
not expected to be efficient in an O2 atmosphere due to inacti- vation caused by oxidation.18 Further, they indeed provided no yields (Table 1; for detailed yields, see ESI, Tables S2–S11†). In addition, all the tested Cu salts satisfactorily performed with $ yields over 75% (e.g., Cu(BF4)2 2H2O: 82%; CuF2: 81%; CuCl2- $ 2H2O: 80%), among which Cu(acac)2 gave the highest yield of 2a (Table S12†).
2.2 Optimized dosage of Cu(acac)2 and neocuproine
Aer conrming the suitable combination of Cu(acac)2 and
neocuproine, the optimized ratio of Cu(acac)2 and neocuproine ligand was explored, as shown in Fig. 1A. Originally, the relative molar ratio of [Cu] vs. ligand was set at 1 vs. 1. As expected, the yields were higher when the loading values were higher (from 20% at 0.4 equiv. : 0.4 equiv. to 46% at 1 equiv. : 1 equiv.). However, aer each loading was above 1 equiv., the yields
Creative Commons Attribution 3.0 Unported Licence. stopped increasing (maintaining 46% at 1.5 equiv.). Then, the loading of neocuproine was adjusted further as the dosage of
Cu(acac)2 was xed at 1 equiv. As shown in Fig. 1A, when the loadings of neocuproine were 0.8, 1.0, 1.2, and 1.5 equiv., the yields were 31%, 46%, 68%, and 85%, respectively. This implied the strong dependency of neocuproine dosage in the system. However, a further increase in the neocuproine dosage to 1.8 equiv. did not help in increasing the yield. Finally, the loading was doubled as 2 equiv. : 3 equiv., and the yield was still This article is licensed under a Scheme 2 Different strategies for the syntheses of cyclic imides. unimproved. Therefore, the optimized dosage of Cu(acac)2 and neocuproine was 1 equiv. vs. 1.5 equiv.
ff Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. 2.3 E ects of solvents and sustainable chemistry, oxidants such as inorganic salts, ff IBX, oxone, BQ TBHP, DDQ, or PhI(OAc)2 su er from many Solvents acted as the reaction media and intensively in uenced problems such as waste disposal, high cost, and poor atom the catalytic reactions.30–34 The effects of nine representative economy. solvents on the catalytic reaction were tested, and the results Encouraged by the recently published articles and our were summarized, as shown in Fig. 1B. Five nonpolar solvents interest in nonnoble-metal-catalyzed oxidization and cycliza- were tested. Tetrahydrofuran (THF) and acetone showed nearly tion reactions, herein, we developed an efficient, copper-based no activity in the system. Nitromethane (MeNO2) and 1,4- catalytic system comprising commercially available Cu salts dioxane started to show some reactive abilities. Surprisingly, and a bidentate nitrogen ligand for the preparation of cyclic when the solvent was switched to MeCN, the highest yield was imides from alkene-tethered amides in acetonitrile (MeCN) 85%. In addition, three high-boiling-point polar aprotic 20–22 under atmospheric O2 at 100 C. solvents, namely, dimethyl sulfoxide (DMSO), dimethyl form- amide (DMF), and 1,3-dimethyl-2-imidazolidinone (DMI), were tested, but they yielded nearly no products. Finally, we tried 2. Results and discussion ethanol (EtOH) as a protic solvent, and it showed a medium 2.1 Screening of metal salts and ligands yield. Without doubt, MeCN was considered to be the most Metal salts coordinated with specic ligands exhibit excellent suitable solvent for this system. catalytic abilities.23–29 In the initial set of experiments, a series of ff frequently used metal salts coordinated with ligands 2.4 E ects of temperature containing N, P, or other elements were tested, and the results To gain more specic information regarding the catalytic are shown in Table 1. Here, 10 types of transition metal salts (Fe, system, the reaction temperatures were set from 30 to 110 C Co, Ni, Cu, Zn, Mn, Pd, Ru, Rh, and Ir salts) with 22 types of (shown in Fig. 1C). Here, 30 and 40 C were too low to provide ligands (for detailed information, see ESI, Table S1†) were sufficient energy for the reaction. Temperatures ranging from
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Table 1 Metal-catalyzed oxygenation of alkene-tethered amides to 5-oxo-4-phenylpyrrolidine-2-carbaldehyde) was detected and a cyclic imides recorded (shown in Fig. 1D). A clear initial increase in the aldehyde concentration was observed, and consumption subsequently occurred. In addition, the amount of 1a sharply decreased in the initial phase (for detailed information of the quantitative data, see ESI, Table S15†).
2.6 Effects of additives In order to further increase the yield and efficiency of the b Entry Metal salt Ligand Yield /% reaction, 10 types of additives were tested (shown in Table 2).
c Unfortunately, none of them yielded better results. However, 1 FeCl3$6H2O A–V <1% $ – c the incorporation of H2O did not reduce the yield, which 2 Co(BF4)2 6H2O A V <5% – c 3 Ni(acac)2 A V <1% implied that the catalytic system was robust against water and – c 4 Cu(acac)2 A V Up to 85% therefore could be applied to more industrial scenes. c 5 ZnCl2 A–V <1% $ – c 6 MnCl2 4H2O A V <1% c 7 PdCl2 A–V <6% 2.7 Authentication of component necessity in the catalytic – c 8 RuCl3 A V <5% system $ – c 9 RhCl3 3H2O A V <6% – c A series of control experiments were conducted with the lack of 10 IrCl3 A V <4% Cu salt, ligand, or O2 to conrm the indispensability of each component (Table S14†). Further, the results showed that
without the Cu salt, ligand, or O2, the reaction could not Creative Commons Attribution 3.0 Unported Licence. proceed at all.
2.8 Scaled-up experiment Importantly, we conducted a large-scale experiment (larger by 10 times) and obtained a yield of 66% over 24 h and 78% over 36 h, indicating that our system can nd valuable applications in industrial production, as shown in Scheme 3. This article is licensed under a 2.9 Substrate scope On the basis of the optimized reaction conditions, the scope of this transformation was explored, as shown in Scheme 4. To our Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. delight, ethoxy could be well preserved during the entire process. Moderate to good yields were obtained, with the highest isolated yield of 84% (2a). A phenyl group in the molecular chain seemed to be in favor of the transformation (2b, 2c, and 2d vs. 2e and 2g) perhaps due to the stabilization a Reaction conditions: 1a, 0.1 mmol; metal salt, 0.01 mmol (10 mol%); 35 effect of the aromatic ring in the reaction course. Substitution ligand, 0.015 mmol (15 mol%); MeCN, 1.5 mL; O2 (1 atm); 100 C; 24 h. b Determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as the beta to the amide led to a substantial decrease in the reaction internal standard. c For detailed yields, see ESI, Tables S2–S11. yield even aer longer reaction times (2f), presumably due to steric hindrance. Substrates with 4-, 5-, and 6-membered spi- rocycles in the alpha position could be tolerated, but with relatively lower yields (2h, 2i, 2j, and 2k). The 1l-containing 50 to 100 C started to give satisfactory yields: a higher conjugated alkene structure could be translated into 2l, but with temperature was associated with a higher yield. However, when a low yield (48 h) maybe because of the unanticipated oxidation the temperature was further improved to 110 C, the yield was process in the O2 atmosphere at 100 C. slightly reduced perhaps due to the side reactions induced by To explore the versatility of this catalytic system, it was used the higher temperature. Therefore, 100 C was considered to be to prepare glutarimide derivatives. Before that, we retested the the optimal temperature for this system. copper salts and found that the best one was CuF2 (Table S13, ESI†). Further, a new round of substrate scope was demon- strated in Scheme 3. Products with a 6-membered ring exhibited 2.5 Kinetic study lower yields (4a–4g,49–63%) owing to the lower stability than We conducted kinetic observations; the amounts of 1a and 2a the 5-membered ones.36 Similarly, 3h bearing a conjugated were recorded and an aldehyde intermediate (1-ethoxy-4-ethyl- alkene structure still performed poorly (Scheme 5).
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Fig. 1 Oxygenation of alkene-tethered amides to cyclic imides using O2 catalyzed by Cu(acac)2 and neocuproine ligand system. Reaction conditions: 1a, 0.1 mmol; Cu(acac)2, 0.01 mmol (10 mol%); neocuproine, 0.015 mmol (15 mol%); MeCN, 1.5 mL; O2 (1 atm); 100 C; 24 h; unless otherwise stated. Yields were determined by 1H NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard (A) effects of dosage of
Cu(acac)2 and neocuproine ligand (numbers denote the loading values of Cu(acac)2 and neocuproine in equiv. relative to substrate 1a); (B) effects of solvents; (C) effects of temperature; (D) kinetic analysis. This article is licensed under a
2.10 Reaction mechanism coordinated with the N-ligand neocuproine to form the cata-
Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. lytically active species [Cu(II)]/L. [Cu(II)]/L replaced a proton in In order to investigate the possible reaction mechanism, some substrate 1a generating A, and the cis-amidocupration of the control experiments and isotope-labeling experiments were alkene occurred, affording organo-copper(II) intermediate B.In conducted (Scheme 6). Two types of radical scavengers, namely, the next step, oxygen molecules participated in the process and (2,2,6,6-tetramethylpiperidin-1-yl)oxyl (TEMPO) and 1,1-diphe- radical (C) was formed via the homolysis of the C–Cu bond.37,39 nylethylene, were employed to explore whether the trans- The generation of C from B was achieved via a radical species formation involved free radicals or not. The extremely low yields (for detailed process, see ESI, Scheme S1†). Then, the 1,3- of 2a indicated that the free radicals participated in the process, – which was doubtlessly consistent with earlier reports hydrogen migration and homolysis of the O O bond generated – intermediate E, which could be detected in the system. A (Scheme 6a and b).35,37 39 Compound E was detected in the combination of [Cu(II)]/L and transfer of electrons afforded G. system and was considered to be an intermediate. Therefore, E 18 Finally, another oxygen molecule was inserted, and product 2a was used as the substrate and O2 was replaced by O2 to track 0 was formed aer intramolecular electron transfer, releasing CO the O source. Further, product 2a with isotope-labeling was 38 18 at the same time. produced, as detected by HR-ESI (Scheme 6c). In addition, C O was conrmed using GC-MS. Finally, a proof experiment was conducted (Scheme 6d). In conclusion, O2 took part in the 3. Conclusions reaction and became a carbonyl group in the nal product; 18 here, C O was detected again. Summarily, a homogeneous Cu(II) catalytical system was set up Considering the experimental results and earlier reports for the preparation of cyclic imides from alkene-tethered – involving this type of metal/ligand system,35,40 45 a possible amides. In this environmentally friendly reaction pathway, no ffi reaction pathway was proposed, as shown in Scheme 7. For expensive catalyst was employed. O2 was used as an e cient precision and emphasis, the acac anion was omitted and and easily available terminal oxidant. Products containing therefore the electric charges were not shown. Copper salts succinimide and glutarimide structures can nd wide
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Table 2 Cu(acac)2-catalyzed oxygenation of alkene-tethered amides 4.2 Instrumentation to cyclic imidesa 1 Liquid H NMR spectra were obtained in CDCl3 using the residual CHCl3 as the internal reference (7.26 ppm) using a Bruker 400 spectrometer. 1H NMR peaks were labeled as singlet (s), doublet (d), triplet (t), quartet (q), and multiplet (m). The coupling constant values were reported in Hertz (Hz). 13 Liquid C NMR spectra were conducted at 100 MHz in CDCl3
using residual CHCl3 as the internal reference (77.0 ppm). GC- MS analysis was performed using gas chromatography-mass Entry Additive Dosageb Yieldc/% spectrometry (GC-MS, 7890A and 5975C, Agilent). High- resolution electrospray ionization mass spectrometry (HR-ESI- 1K2CO3 1 equiv. 18 MS) was performed on a Bruker FT-ICR-MS instrument 2 KOAc 1 equiv. 22 3 DBU 1 equiv. 58 (Solarix 9.4T). 4 BMImAc 1.5 equiv. 62 5 BMImBr 1.5 equiv. 59 4.3 Synthesis of substrates 6 n-Bu4NF 1.2 equiv. 51 7 PhCOOH 1 equiv. 45 Taking the synthesis of 2-ethyl-N-ethyoxy-2-phenylpent-4- 8 Methylsulfonic acid 1 equiv. 52 enamide (1a) as the example, the procedure was as follows. 9 Acetic anhydride 1 equiv. 48 According to the reported processes,41,46 freshly made lithium 10 H2O 5 equiv. 83 diisopropylamide (LDA, 12.5 mmol) was mixed with a pre- a Reaction conditions: 1a, 0.1 mmol; Cu(acac)2, 0.01 mmol (10 mol%); prepared solution of 2-phenylbutanoic acid (10 mmol) in ligand neocuproine, 0.015 mmol (15 mol%); MeCN, 1.5 mL; O2 (1 10 mL extra dry THF at 0 and 40 C and maintained for 2 h. Aer atm); 100 C; 24 h. b Dosage of additives was relative to 1a. c 1 that, allyl bromide (18 mmol) was added dropwise and the Creative Commons Attribution 3.0 Unported Licence. Determined by H NMR analysis using 1,1,2,2-tetrachloroethane as the internal standard; DBU ¼ 1,8-diazabicyclo[5.4.0]undec-7-ene; solution was stirred for 2.5 h. Liquid separation aer dilution ¼ ¼ BMImBr 1-butyl-3-methylimidazolium bromide; BMImAc 1-butyl- (diethyl ether/water), extraction aer acidication (water 3-methylimidazolium acetate. phase), and column chromatography on the silica gel afforded 2-ethyl-2-phenylpent-4-enoic acid for use in the subsequent step. Oxalyl chloride (12.5 mmol) was added dropwise into a solution of 2-ethyl-2-phenylpent-4-enoic acid (10 mmol) in
CH2Cl2 (10 mL) followed by adding a catalytic amount of DMF. Aer stirring for 2 h, the solvent was removed via a rotary
This article is licensed under a evaporator. The remnant solid was slowly added to a mixture of
EtONH2$HCl (15 mmol) and K2CO3 (20 mmol) in EtOAc and H2O (2 : 1). A er another 2 h, the organic phase was collected and the target compound in the aqueous phase was extracted by Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. EtOAc. Washing, desiccation, ltration, and column chroma- Scheme 3 Scaled-up experiment. tography afforded the target compound of 2-ethyl-N-ethyoxy-2- phenylpent-4-enamide (1a).
applications in pharmaceutical syntheses along with success- 4.4 General procedure for the reaction of alkene-tethered fully scaled-up experiments. Finally, a possible reaction amides to cyclic imides pathway was proposed and veried by control experiments and Substrate (0.1 mmol), copper salts (0.01 mmol), ligand (0.015 isotope-labeling experiments. We believe that our catalytic mmol), and solvent (1.5 mL) were successively loaded into
system has academic and practical worth, and further investi- a reactor; then, the reactor was connected to an O2 balloon. gations on the cascade amidoarylation of unactivated olens Next, the reactor was moved into an oil bath maintained at the catalyzed by copper complexes are ongoing. desired temperature (e.g., 100 C) and stirred for 24 h. Aer this reaction, the reactor was cooled down to room temperature. The products were isolated by column chromatography on silica gel using n-hexane/ethyl acetate as the eluent and their NMR and 4. Experimental MS spectra were obtained. 4.1 Materials Metal salts, ligands, additives, raw materials, and solvents were 4.5 Characterization data of substrates, products, and purchased from Sinopharm Chemical Reagent Co, J&K Chem- reaction intermediates icals, or Sigma-Aldrich. Materials obtained from commercial N-Ethoxy-2-ethyl-2-phenylpent-4-enamide (1a). 1H NMR (400 resources were used without further purication unless other- MHz, chloroform-d) d 7.39–7.30 (m, 4H), 7.29–7.22 (m, 1H), 7.20 wise noted. (s, 1H), 5.78 (m, 1H), 5.24–5.17 (m, 1H), 5.17–5.12 (m, 1H), 3.72
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N-Ethoxy-2,2-diethylpent-4-enamide (1c). 1H NMR (400 MHz, chloroform-d) d 7.45 (s, 1H), 5.77 (m, 1H), 5.15 (m, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.32 (m, 2H), 1.71 (m, 4H), 1.19 (t, J ¼ 8.0 Hz, 3H), 0.87 (t, J ¼ 8.0 Hz, 6H); 13C{1H} NMR (100 MHz, chloroform-d) d 175.99, 134.68, 118.15, 67.96, 49.62, 41.30, 28.04, 12.95, 8.66; + HRMS (ESI) m/z calcd for C11H22NO2 [M + H] 200.1645, found 200.1651. N-Ethoxy-2-ethyl-2-methylpent-4-enamide (1d). 1H NMR (400 MHz, chloroform-d) d 7.47 (s, 1H), 5.77 (m, 1H), 5.15 (m, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.32 (m, 1H), 2.25 (m, 1H), 1.63 (q, J ¼ 7.9 Hz, 2H), 1.20 (t, J ¼ 8.0 Hz, 3H), 1.15 (s, 3H), 0.89 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 175.02, 134.92, 118.03, 67.89, 46.68, 42.40, 29.25, 20.35, 12.95, 9.07; + HRMS (ESI) m/z calcd for C10H20NO2 [M + H] 186.1489, found 186.1483. N-Ethoxy-2-methyl-2-phenylpent-4-enamide (1e). 1H NMR (400 MHz, chloroform-d) d 7.39–7.31 (m, 2H), 7.31–7.23 (m, 3H), 7.22 (s, 1H), 5.78 (m, 1H), 5.18 (m, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.77–2.65 (m, 2H), 1.45 (s, 3H), 1.18 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 173.43, 141.28, 132.81, 128.46, a Scheme 4 Substrate scope (for succinimide derivatives). Reaction 127.63, 126.55, 118.22, 67.96, 47.46, 41.63, 23.47, 12.96; HRMS conditions: substrate, 0.1 mmol; Cu(acac)2, 0.01 mmol (10 mol%); + (ESI) m/z calcd for C14H20NO2 [M + H] 234.1489, found neocuproine, 0.015 mmol (15 mol%); MeCN, 1.5 mL; O2 (1 atm); b c Creative Commons Attribution 3.0 Unported Licence. 234.1492. 100 C; 24 h. Isolated yields. 48 h. N-Ethoxy-2,3-diethyl-2-phenylpent-4-enamide (1f). 1H NMR (400 MHz, chloroform-d) d 7.47 (s, 1H), 7.38–7.23 (m, 5H), 5.80 (m, 1H), 5.25–5.15 (m, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.86 (m, 1H), 2.01 (q, J ¼ 8.0 Hz, 2H), 1.39–1.26 (m, 2H), 1.18 (t, J ¼ 8.0 Hz, 3H), 0.90 (m, 6H); 13C{1H} NMR (100 MHz, chloroform-d) d 175.16, 141.80, 137.59, 128.46, 127.58, 127.35, 117.10, 67.96, 57.83, 48.83, 28.95, 24.81, 12.95, 11.65, 8.82; HRMS (ESI) m/z + calcd for C17H26NO2 [M + H] 276.1958, found 276.1955. This article is licensed under a N-Ethoxy-2,2-diphenylpent-4-enamide (1g). 1H NMR (400 MHz, chloroform-d) d 7.39–7.32 (m, 4H), 7.32–7.24 (m, 6H), 6.96 (s, 1H), 5.89 (m, 1H), 5.24 (m, 1H), 5.17 (m, 1H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.75 (m, 2H), 1.17 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. (100 MHz, chloroform-d) d 173.14, 141.72, 132.24, 128.24, 128.06, 127.64, 118.56, 67.96, 58.67, 44.32, 12.95; HRMS (ESI) m/ + z calcd for C19H22NO2 [M + H] 296.1645, found 296.1641. 1-Allyl-N-ethoxycyclobutane-1-carboxamide (1h). 1H NMR a d Scheme 5 Substrate scope (for glutarimide derivatives). Reaction (400 MHz, chloroform-d) 7.88 (s, 1H), 5.76 (m, 1H), 5.17 (m, ¼ – conditions: substrate, 0.1 mmol; CuF2, 0.01 mmol (10 mol%); neo- 1H), 5.12 (m, 1H), 3.72 (q, J 8.0 Hz, 2H), 2.28 (m, 2H), 2.04 cuproine, 0.015 mmol (15 mol%); MeCN, 1.5 mL; O2 (1 atm); 100 C; 1.92 (m, 4H), 1.77–1.69 (m, 1H), 1.69–1.59 (m, 1H), 1.20 (t, J ¼ b c 24 h. Isolated yields. 48 h. 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 173.47, 134.55, 118.14, 67.89, 51.47, 41.38, 30.94, 17.78, 12.95; HRMS + (ESI) m/z calcd for C10H18NO2 [M + H] 184.1332, found (q, J ¼ 8.0 Hz, 2H), 2.73–2.62 (m, 2H), 1.91 (q, J ¼ 7.9 Hz, 2H), 184.1336. 13 1 1.18 (t, J ¼ 8.0 Hz, 3H), 0.87 (t, J ¼ 8.0 Hz, 3H); C{H} NMR 1-Allyl-N-ethoxycyclopentane-1-carboxamide (1i). 1H NMR (100 MHz, chloroform-d) d 174.00, 141.54, 132.73, 128.59, (400 MHz, chloroform-d) d 8.07 (s, 1H), 5.76 (m, 1H), 5.16 (m, 127.40, 126.84, 118.10, 67.96, 51.12, 41.63, 29.38, 12.96, 8.90; 1H), 5.11 (m, 1H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.26 (dt, J ¼ 6.2, + HRMS (ESI) m/z calcd for C15H22NO2 [M + H] 248.1645, found 1.0 Hz, 2H), 1.86–1.74 (m, 6H), 1.72–1.64 (m, 2H), 1.19 (t, J ¼ 248.1648. 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 175.14, 1 N-Ethoxy-2,2-dimethylpent-4-enamide (1b). H NMR (400 134.64, 118.24, 67.96, 54.40, 41.09, 35.01, 23.59, 12.95; HRMS d + MHz, chloroform-d) 7.48 (s, 1H), 5.78 (m, 1H), 5.16 (m, 2H), (ESI) m/z calcd for C11H20NO2 [M + H] 198.1489, found 3.72 (q, J ¼ 8.0 Hz, 2H), 2.31 (m, 2H), 1.20 (t, J ¼ 8.0 Hz, 3H), 1.11 198.1493. 13 1 (s, 6H); C{ H} NMR (100 MHz, chloroform-d) d 176.75, 134.30, 1-Allyl-N-ethoxycyclohexane-1-carboxamide (1j). 1H NMR 118.04, 67.92, 44.68, 42.56, 25.10, 12.95; HRMS (ESI) m/z calcd (400 MHz, chloroform-d) d 8.07 (s, 1H), 5.76 (m, 1H), 5.17 (m, + for C9H18NO2 [M + H] 172.1332, found 172.1327.
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(q, J ¼ 8.0 Hz, 2H), 1.19 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 166.56, 135.88, 133.60, 130.72, 130.45, 128.64, 127.45, 127.02, 117.60, 68.02, 12.95; HRMS (ESI) m/z + calcd for C11H14NO2 [M + H] 192.1019, found 192.1023. 1-Ethoxy-3-ethyl-3-phenylpyrrolidine-2,5-dione (2a). 1H NMR (400 MHz, chloroform-d) d 7.37–7.29 (m, 4H), 7.29–7.21 (m, 1H), 3.88 (q, J ¼ 8.0 Hz, 2H), 3.01–2.91 (m, 2H), 2.25 (m, 1H), 1.75 (m, 1H), 1.20 (t, J ¼ 8.0 Hz, 3H), 0.87 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 178.38, 169.68, 141.37, 128.72, 127.46, 126.74, 66.92, 49.63, 42.99, 29.04, 13.28, 9.30; HRMS + (ESI) m/z calcd for C14H18NO3 [M + H] 248.1281, found 248.1273. 1-Ethoxy-3,3-dimethylpyrrolidine-2,5-dione (2b). 1H NMR (400 MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.60 (s, 2H), 1.26 (s, 6H), 1.22 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 174.79, 170.53, 66.83, 43.03, 40.86, 26.41, 13.31; + HRMS (ESI) m/z calcd for C8H14NO3 [M + H] 172.0968, found 172.0972. 1-Ethoxy-3,3-diethylpyrrolidine-2,5-dione (2c). 1H NMR (400 MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.63 (s, 1H), 2.56 (s, 1H), 1.88–1.70 (m, 4H), 1.21 (t, J ¼ 8.0 Hz, 3H), 0.88 (t, J ¼ a 13 1 Scheme 6 Mechanism research. Reaction conditions: substrate, 8.0 Hz, 6H); C{H} NMR (100 MHz, chloroform-d) d 177.06, 0.1 mmol; Cu(acac) , 0.01 mmol (10 mol%); neocuproine, 0.015 mmol Creative Commons Attribution 3.0 Unported Licence. 2 171.12, 66.90, 48.68, 40.58, 27.91, 13.30, 8.60; HRMS (ESI) m/z (10 mol%); MeCN, 1.5 mL; O (1 atm); 100 C; 24 h. + 2 calcd for C10H18NO3 [M + H] 200.1281, found 200.1275. 1-Ethoxy-3-ethyl-3-methylpyrrolidine-2,5-dione (2d). 1H NMR (400 MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.56 (d, J ¼ 1H), 5.10 (dq, J ¼ 13.4, 1.0 Hz, 1H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.25 12.4 Hz, 1H), 2.51 (d, J ¼ 12.4 Hz, 1H), 1.64 (q, J ¼ 8.0 Hz, 2H), (m, 2H), 1.79 (t, J ¼ 6.8 Hz, 4H), 1.66–1.56 (m, 4H), 1.56–1.46 (m, 1.26–1.18 (m, 6H), 0.88 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 2H), 1.19 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloro- MHz, chloroform-d) d 175.03, 170.65, 66.84, 43.38, 41.30, 29.19, d + form-d) 175.53, 134.56, 118.24, 67.97, 48.45, 40.96, 33.41, 20.69, 13.30, 9.18; HRMS (ESI) m/z calcd for C9H16NO3 [M + H] 25.60, 23.25, 12.96; HRMS (ESI) m/z calcd for C12H22NO2 [M + 186.1125, found 186.1114.
This article is licensed under a H]+ 212.1645, found 212.1649. 1-Ethoxy-3-methyl-3-phenylpyrrolidine-2,5-dione (2e). 1H N-Ethoxy-2-vinylcyclohexane-1-carboxamide (1k). 1H NMR NMR (400 MHz, chloroform-d) d 7.38–7.31 (m, 2H), 7.31–7.22 (400 MHz, chloroform-d) d 8.40 (s, 1H), 5.79 (m, 1H), 5.20 (m, (m, 3H), 3.88 (q, J ¼ 8.0 Hz, 2H), 2.94 (d, J ¼ 1.5 Hz, 2H), 1.58 (s, 1H), 5.14 (m, 1H), 3.71 (q, J ¼ 8.0 Hz, 2H), 2.77 (m, 1H), 2.57 (q, J 3H), 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloro- Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. ¼ 7.0 Hz, 1H), 1.74–1.50 (m, 8H), 1.19 (t, J ¼ 8.0 Hz, 3H); 13C form-d) d 174.42, 169.74, 142.30, 128.68, 127.68, 126.04, 66.92, 1 d { H} NMR (100 MHz, chloroform-d) 173.39, 139.80, 115.37, 46.96, 45.20, 24.22, 13.29; HRMS (ESI) m/z calcd for C13H16NO3 68.18, 47.38, 39.81, 30.29, 26.60, 24.62, 24.47, 12.95; HRMS (ESI) [M + H]+ 234.1125, found 234.1133. + 1 m/z calcd for C11H20NO2 [M + H] 198.1489, found 198.1492. 1-Ethoxy-3,4-diethyl-3-phenylpyrrolidine-2,5-dione (2f). H N-Ethoxy-2-vinylbenzamide (1l). 1H NMR (400 MHz, chloro- NMR (400 MHz, chloroform-d) d 7.37–7.30 (m, 2H), 7.30–7.23 form-d) d 9.55 (s, 1H), 7.75–7.70 (m, 1H), 7.51–7.43 (m, 2H), (m, 3H), 3.89 (m, 2H), 3.15 (m, 1H), 2.25–2.14 (m, 1H), 2.14–2.06 7.43–7.38 (m, 1H), 7.12 (m, 1H), 5.69 (m, 1H), 5.55 (m, 1H), 3.73 (m, 1H), 1.67 (m, 1H), 1.56 (m, 1H), 1.20 (t, J ¼ 8.0 Hz, 3H), 1.00
Scheme 7 Proposed mechanism.
7704 | RSC Adv.,2020,10, 7698–7707 This journal is © The Royal Society of Chemistry 2020 View Article Online Paper RSC Advances
(m, 3H), 0.92 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, 33.43, 29.67, 28.32, 12.96, 8.61; HRMS (ESI) m/z calcd for d + chloroform-d) 175.46, 171.98, 139.38, 128.63, 127.66, 126.55, C12H24NO2 [M + H] 214.1802, found 214.1806. 66.97, 51.64, 46.31, 29.95, 18.55, 13.28, 12.66, 8.76; HRMS (ESI) N-Ethoxy-2-methyl-2-phenylhex-5-enamide (3c). 1H NMR + d – – m/z calcd for C16H22NO3 [M + H] 276.1594, found 276.1598. (400 MHz, chloroform-d) 7.39 7.32 (m, 2H), 7.31 7.23 (m, 4H), 1-Ethoxy-3,3-diphenylpyrrolidine-2,5-dione (2g). 1H NMR 5.75 (m, 1H), 5.14–5.06 (m, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.28– (400 MHz, chloroform-d) d 7.39–7.32 (m, 4H), 7.32–7.26 (m, 6H), 2.14 (m, 2H), 2.06 (m, 1H), 2.01–1.94 (m, 1H), 1.47 (s, 3H), 1.18 3.88 (q, J ¼ 8.0 Hz, 2H), 3.23 (s, 1H), 3.17 (s, 1H), 1.18 (t, J ¼ (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 173.01, d 173.74, 141.93, 137.77, 128.47, 127.66, 126.74, 114.75, 67.96, 169.19, 139.86, 128.21, 127.58, 126.77, 66.97, 55.51, 44.39, 47.50, 37.50, 28.89, 24.06, 12.96; HRMS (ESI) m/z calcd for + + 13.28; HRMS (ESI) m/z calcd for C19H18NO3 [M + H] 308.1281, C15H22NO2 [M + H] 248.1645, found 248.1642. found 308.1287. N-Ethoxy-2,2-diphenylhex-5-enamide (3d). 1H NMR (400 6-Ethoxy-6-azaspiro[3.4]octane-5,7-dione (2h). 1H NMR (400 MHz, chloroform-d) d 7.40–7.33 (m, 4H), 7.33–7.26 (m, 2H), MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.63 (s, 2H), 2.19– 7.26–7.20 (m, 4H), 7.03 (s, 1H), 5.85–5.73 (m, 1H), 5.09 (dt, J ¼ 2.04 (m, 4H), 1.79–1.61 (m, 2H), 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} 13.4, 1.0 Hz, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.35–2.28 (m, 2H), NMR (100 MHz, chloroform-d) d 173.80, 171.10, 66.84, 50.09, 2.28–2.21 (m, 2H), 1.16 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100
40.05, 31.83, 17.90, 13.29; HRMS (ESI) m/z calcd for C9H14NO3 MHz, chloroform-d) d 172.56, 142.26, 138.04, 128.12, 127.81, [M + H]+ 184.0968, found 184.0964. 127.55, 114.75, 67.96, 57.68, 38.65, 29.59, 12.95; HRMS (ESI) m/z 1 + 2-Ethoxy-2-azaspiro[4.4]nonane-1,3-dione (2i). H NMR (400 calcd for C20H24NO2 [M + H] 310.1802, found 310.1806. MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.61 (s, 2H), 1.88– 1-(But-3-en-1-yl)-N-ethoxycyclobutane-1-carboxamide (3e). 1.74 (m, 8H), 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, 1H NMR (400 MHz, chloroform-d) d 7.95 (s, 1H), 5.73 (m, 1H), chloroform-d) d 175.09, 170.67, 66.90, 47.93, 42.19, 36.21, 23.27, 5.05 (dt, J ¼ 13.5, 1.1 Hz, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.16–1.96 + 13.30; HRMS (ESI) m/z calcd for C10H16NO3 [M + H] 198.1125, (m, 6H), 1.78–1.62 (m, 2H), 1.59 (t, J ¼ 7.1 Hz, 2H), 1.19 (t, J ¼ 13 1 d
Creative Commons Attribution 3.0 Unported Licence. found 198.1129. 8.0 Hz, 3H); C{H} NMR (100 MHz, chloroform-d) 173.78, 2-Ethoxy-2-azaspiro[4.5]decane-1,3-dione (2j). 1H NMR (400 137.79, 114.73, 67.96, 51.08, 33.98, 31.25, 29.62, 17.14, 12.95; + MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.64 (s, 2H), 1.89– HRMS (ESI) m/z calcd for C11H20NO2 [M + H] 198.1489, found 1.81 (m, 2H), 1.75 (m, 2H), 1.69–1.55 (m, 4H), 1.55–1.46 (m, 2H), 198.1485. 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) 1-(But-3-en-1-yl)-N-ethoxycyclopentane-1-carboxamide (3f). d 175.02, 170.89, 66.88, 46.23, 40.02, 32.45, 25.74, 23.01, 13.31; 1H NMR (400 MHz, chloroform-d) d 8.14 (s, 1H), 5.73 (m, 1H), + HRMS (ESI) m/z calcd for C11H18NO3 [M + H] 212.1281, found 5.04 (dt, J ¼ 13.4, 1.0 Hz, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.12 (m, 212.1286. 2H), 1.93–1.85 (m, 2H), 1.85–1.79 (m, 1H), 1.79–1.68 (m, 5H), 2-Ethoxyhexahydro-1H-isoindole-1,3(2H)-dione (2k). 1H 1.58 (t, J ¼ 7.1 Hz, 2H), 1.19 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR
This article is licensed under a NMR (400 MHz, chloroform-d) d 3.88 (m, 2H), 2.87–2.79 (m, 2H), (100 MHz, chloroform-d) d 176.04, 137.73, 114.74, 67.97, 54.40, 1.71–1.53 (m, 6H), 1.53–1.41 (m, 2H), 1.21 (t, J ¼ 8.0 Hz, 3H); 13C 35.77, 35.27, 29.79, 23.64, 12.96; HRMS (ESI) m/z calcd for 1 d + { H} NMR (100 MHz, chloroform-d) 171.99, 67.18, 40.06, 24.98, C12H22NO2 [M + H] 212.1645, found 212.1643. + N 24.71, 13.30; HRMS (ESI) m/z calcd for C10H16NO3 [M + H] 1-(But-3-en-1-yl)- -ethoxycyclohexane-1-carboxamide (3g). Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. 198.1125, found 198.1129. 1H NMR (400 MHz, chloroform-d) d 8.14 (s, 1H), 5.73 (m, 1H), 2-Ethoxyisoindoline-1,3-dione (2l). 1H NMR (400 MHz, 5.06 (dt, J ¼ 13.4, 1.0 Hz, 2H), 3.72 (q, J ¼ 8.0 Hz, 2H), 2.11 (m, chloroform-d) d 7.88–7.83 (m, 2H), 7.79 (m, 2H), 3.99 (q, J ¼ 2H), 1.82–1.70 (m, 4H), 1.65–1.47 (m, 8H), 1.19 (t, J ¼ 8.0 Hz, 8.0 Hz, 2H), 1.20 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 176.60, 137.82, chloroform-d) d 164.75, 133.16, 129.67, 123.31, 70.59, 12.86; 114.74, 67.97, 48.19, 34.60, 33.69, 29.83, 25.70, 23.31, 12.96; + + HRMS (ESI) m/z calcd for C10H10NO3 [M + H] 192.0655, found HRMS (ESI) m/z calcd for C13H24NO2 [M + H] 226.1802, found 1920647. 226.1807. N-Ethoxy-2-ethyl-2-phenylhex-5-enamide (3a). 1H NMR (400 2-Allyl-N-ethoxybenzamide (3h). 1H NMR (400 MHz, chloro- MHz, chloroform-d) d 7.40–7.33 (m, 3H), 7.33–7.29 (m, 1H), form-d) d 8.35 (s, 1H), 7.76 (dd, J ¼ 7.4, 1.5 Hz, 1H), 7.46 (m, 1H), 7.29–7.23 (m, 2H), 5.76 (m, 1H), 5.14–5.06 (m, 2H), 3.72 (q, J ¼ 7.40–7.31 (m, 2H), 5.82 (m, 1H), 5.11 (m, 1H), 5.01 (m, 1H), 3.74 8.0 Hz, 2H), 2.28–2.12 (m, 2H), 2.01–1.92 (m, 1H), 1.92–1.81 (m, (q, J ¼ 8.0 Hz, 2H), 3.47 (dq, J ¼ 6.2, 1.0 Hz, 2H), 1.19 (t, J ¼ 3H), 1.18 (t, J ¼ 8.0 Hz, 3H), 0.86 (t, J ¼ 8.0 Hz, 3H); 13C{1H} 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 165.58, NMR (100 MHz, chloroform-d) d 173.43, 142.46, 137.88, 128.58, 136.70, 136.54, 132.86, 130.08, 129.51, 128.89, 127.57, 116.11,
127.35, 126.63, 114.75, 67.96, 51.20, 35.75, 30.36, 29.37, 12.96, 68.05, 36.36, 12.95; HRMS (ESI) m/z calcd for C12H16NO2 [M + + + 8.89; HRMS (ESI) m/z calcd for C16H24NO2 [M + H] 262.1802, H] 206.1176, found 206.1174. found 262.1799. 1-Ethoxy-3-ethyl-3-phenylpiperidine-2,6-dione (4a). 1H NMR N-Ethoxy-2,2-diethylhex-5-enamide (3b). 1H NMR (400 MHz, (400 MHz, chloroform-d) d 7.39–7.32 (m, 2H), 7.30 (t, J ¼ 1.6 Hz, chloroform-d) d 7.52 (s, 1H), 5.73 (m, 1H), 5.05 (m, 2H), 3.72 (q, J 1H), 7.29–7.22 (m, 2H), 3.88 (m, 2H), 2.62–2.50 (m, 2H), 2.11 (dt, ¼ 8.0 Hz, 2H), 2.11 (m, 2H), 1.80–1.63 (m, 5H), 1.59 (m, 1H), 1.19 J ¼ 12.4, 7.1 Hz, 1H), 2.07–1.92 (m, 2H), 1.92–1.85 (m, 1H), 1.18 (t, J ¼ 8.0 Hz, 3H), 0.87 (t, J ¼ 8.0 Hz, 6H); 13C{1H} NMR (100 (t, J ¼ 8.0 Hz, 3H), 0.84 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) d 175.54, 137.73, 114.74, 67.97, 48.96, MHz, chloroform-d) d 173.73, 167.96, 141.60, 128.59, 127.34,
This journal is © The Royal Society of Chemistry 2020 RSC Adv.,2020,10,7698–7707 | 7705 View Article Online RSC Advances Paper
126.26, 66.92, 47.89, 32.63, 30.37, 30.27, 13.28, 9.45; HRMS (ESI) 1.20 (t, J ¼ 8.0 Hz, 3H), 0.85 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR + d m/z calcd for C15H20NO3 [M + H] 262.1438, found 262.1442. (100 MHz, chloroform-d) 197.34, 174.65, 143.08, 128.59, 1-Ethoxy-3,3-diethylpiperidine-2,6-dione (4b). 1H NMR (400 127.31, 126.28, 65.63, 65.01, 50.54, 40.23, 29.78, 13.28, 9.45; d ¼ ¼ + MHz, chloroform-d) 3.88 (q, J 8.0 Hz, 2H), 2.49 (t, J 7.1 Hz, HRMS (ESI) m/z calcd for C15H20NO3 [M + H] 262.1438, found 2H), 2.02 (t, J ¼ 7.1 Hz, 2H), 1.83–1.68 (m, 4H), 1.21 (t, J ¼ 8.0 Hz, 262.1443. 3H), 0.86 (t, J ¼ 8.0 Hz, 6H); 13C{1H} NMR (100 MHz, chloro- form-d) d 174.37, 167.42, 66.88, 45.25, 31.55, 30.46, 27.87, 13.31, fl + Con icts of interest 8.50; HRMS (ESI) m/z calcd for C11H20NO3 [M + H] 214.1438, found 214.1435. There are no conicts to declare. 1-Ethoxy-3-methyl-3-phenylpiperidine-2,6-dione (4c). 1H NMR (400 MHz, chloroform-d) d 7.38–7.31 (m, 2H), 7.29–7.21 Acknowledgements (m, 3H), 3.88 (m, 2H), 2.62–2.49 (m, 2H), 2.21–2.06 (m, 2H), 1.52 (s, 3H), 1.18 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chlo- We thank the National Natural Science Foundation of China roform-d) d 172.40, 167.97, 142.32, 128.47, 127.66, 126.21, 66.92, (21773307), Zhejiang Provincial Natural Science Foundation of 45.32, 33.70, 29.90, 24.64, 13.28; HRMS (ESI) m/z calcd for China (LTY20B050001) and Zhejiang Provincial Basic Public + C14H18NO3 [M + H] 248.1281, found 248.1279. Welfare Research Project (LGG19B060002). 1-Ethoxy-3,3-diphenylpiperidine-2,6-dione (4d). 1H NMR (400 MHz, chloroform-d) d 7.39–7.32 (m, 4H), 7.32–7.25 (m, 2H), References 7.25–7.20 (m, 4H), 3.88 (q, J ¼ 8.0 Hz, 2H), 2.58–2.52 (m, 2H), 2.27 (m, 2H), 1.15 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, 1 M. S. Sherikar and K. R. Prabhu, Org. Lett., 2019, 21, 4525– chloroform-d) d 169.72, 167.94, 141.45, 128.14, 127.55, 126.72, 4530. 66.99, 55.54, 35.03, 29.72, 13.28; HRMS (ESI) m/z calcd for 2 N. Barsu, D. Kalsi and B. Sundararaju, Catal. Sci. Technol., + –
Creative Commons Attribution 3.0 Unported Licence. C19H20NO3 [M + H] 310.1438, found 310.1435. 2018, 8, 5963 5969. 6-Ethoxy-6-azaspiro[3.5]nonane-5,7-dione (4e). 1H NMR (400 3 M. Milan, G. Carboni, M. Salamone, M. Costas and M. Bietti, MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.51 (t, J ¼ 7.1 Hz, ACS Catal., 2017, 7, 5903–5911. 2H), 2.15–2.11 (m, 1H), 2.09 (d, J ¼ 7.1 Hz, 1H), 2.05 (d, J ¼ 4 C. S. Digwal, U. Yadav, P. V. S. Ramya, S. Sana, B. Swain and 7.1 Hz, 1H), 2.04–2.01 (m, 1H), 1.99 (t, J ¼ 7.1 Hz, 2H), 1.68 (q, J A. Kamal, J. Org. Chem., 2017, 82, 7332–7345. ¼ 7.2 Hz, 2H), 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, 5 S. K. Singh, N. Chandna and N. Jain, Org. Lett., 2017, 19, chloroform-d) d 171.71, 167.42, 66.90, 45.69, 32.39, 30.73, 29.81, 1322–1325. + 17.28, 13.30; HRMS (ESI) m/z calcd for C10H16NO3 [M + H] 6 J. Streuff, C. H. Hovelmann, M. Nieger and K. Muniz, J. Am. 198.1125, found 198.1129. Chem. Soc., 2005, 127, 14586–14587.
This article is licensed under a 7-Ethoxy-7-azaspiro[4.5]decane-6,8-dione (4f). 1H NMR (400 7 K. Muniz, C. H. Hovelmann and J. Streuff, J. Am. Chem. Soc., MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.50 (t, J ¼ 7.1 Hz, 2008, 130, 763–773. 2H), 2.01–1.86 (m, 4H), 1.82–1.74 (m, 4H), 1.74–1.63 (m, 2H), 8 A. Iglesias, E. G. Perez and K. Muniz, Angew. Chem., Int. Ed., 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloroform-d) 2010, 49, 8109–8111. Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM. d 172.79, 167.42, 66.88, 50.52, 33.73, 33.33, 30.40, 23.49, 13.31; 9 G. Yin, X. Mu and G. Liu, Acc. Chem. Res., 2016, 49, 2413– + HRMS (ESI) m/z calcd for C11H18NO3 [M + H] 212.1281, found 2423. 212.1284. 10 R. Ito, N. Umezawa and T. Higuchi, J. Am. Chem. Soc., 2005, 2-Ethoxy-2-azaspiro[5.5]undecane-1,3-dione (4g). 1H NMR 127, 834–835. (400 MHz, chloroform-d) d 3.88 (q, J ¼ 8.0 Hz, 2H), 2.50 (t, J ¼ 11 K. M. Driller, H. Klein, R. Jackstell and M. Beller, Angew. 7.1 Hz, 2H), 1.97 (t, J ¼ 7.1 Hz, 2H), 1.86–1.73 (m, 4H), 1.66–1.47 Chem., Int. Ed., 2009, 48, 6041–6044. (m, 6H), 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, 12 M. A. Ali, S. K. Moromi, A. S. Touchy and K.-i. Shimizu, chloroform-d) d 173.99, 168.03, 66.92, 42.92, 32.89, 32.23, 30.40, ChemCatChem, 2016, 8, 891–894.
25.74, 22.91, 13.29; HRMS (ESI) m/z calcd for C12H20NO3 [M + 13 P. Williamson, A. Galvan and M. J. Gaunt, Chem. Sci., 2017, 8, H]+ 226.1438, found 226.1443. 2588–2591. 2-Ethoxyisoquinoline-1,3(2H,4H)-dione (4h). 1H NMR (400 14 L. Zeng, H. Li, S. Tang, X. Gao, Y. Deng, G. Zhang, C.-W. Pao, MHz, chloroform-d) d 7.62 (m, 1H), 7.51 (m, 1H), 7.43 (m, 1H), J.-L. Chen, J.-F. Lee and A. Lei, ACS Catal., 2018, 8, 5448– 7.40–7.35 (m, 1H), 3.89 (q, J ¼ 8.0 Hz, 2H), 3.44 (d, J ¼ 1.0 Hz, 5453. 2H), 1.21 (t, J ¼ 8.0 Hz, 3H); 13C{1H} NMR (100 MHz, chloro- 15 Y. Zhang, D. Riemer, W. Schilling, J. Kollmann and S. Das, form-d) d 172.53, 162.88, 135.20, 131.03, 129.81, 127.44, 126.49, ACS Catal., 2018, 8, 6659–6664.
125.53, 67.01, 35.82, 13.31; HRMS (ESI) m/z calcd for C11H12NO3 16 N. Z. Burns, P. S. Baran and R. W. Hoffmann, Angew. Chem., [M + H]+ 206.0812, found 206.0809. Int. Ed., 2009, 48, 2854–2867. 1-Ethoxy-4-ethyl-5-oxo-4-phenylpyrrolidine-2-carbaldehyde 17 K. Dong, X. Fang, S. Gulak,¨ R. Franke, A. Spannenberg, (intermediate E). 1H NMR (400 MHz, chloroform-d) d 9.77 (d, J ¼ H. Neumann, R. Jackstell and M. Beller, Nat. Commun., 6.2 Hz, 1H), 7.38–7.32 (m, 2H), 7.31–7.22 (m, 3H), 4.19 (td, J ¼ 2017, 8, 14117–14123. 7.0, 6.2 Hz, 1H), 3.78 (q, J ¼ 8.0 Hz, 2H), 2.53 (dd, J ¼ 12.4, 18 D. Wang, A. B. Weinstein, P. B. White and S. S. Stahl, Chem. 7.0 Hz, 1H), 2.47 (dd, J ¼ 12.4, 7.0 Hz, 1H), 2.01–1.84 (m, 2H), Rev., 2018, 118, 2636–2679.
7706 | RSC Adv.,2020,10, 7698–7707 This journal is © The Royal Society of Chemistry 2020 View Article Online Paper RSC Advances
19 Z. Shi, C. Zhang, C. Tang and N. Jiao, Chem. Soc. Rev., 2012, 33 H. Zhao, J. E. Holladay, H. Brown and Z. C. Zhang, Science, 41, 3381–3430. 2007, 316, 1597–1600. 20 W. Schilling, Y. Zhang, D. Riemer and S. Das, Chem.–Eur. J., 34 Z. Liu, Z. Yang, P. Wang, X. Yu, Y. Wu, H. Wang and Z. Liu, 2020, 26, 390–395. ACS Sustainable Chem. Eng., 2019, 7, 18236–18241. 21 J. Li, J. Wei, B. Zhu, T. Wang and N. Jiao, Chem. Sci., 2019, 10, 35 T. Wdowik and S. R. Chemler, J. Am. Chem. Soc., 2017, 139, 9099–9103. 9515–9518. 22 Y. Zhang, W. Schilling and S. Das, ChemSusChem, 2019, 12, 36 S. Hu, Z. Zhang, J. Song, Y. Zhou and B. Han, Green Chem., 2898–2910. 2009, 11, 1746–1749. 23 Z. Liu, Z. Yang, X. Yu, H. Zhang, B. Yu, Y. Zhao and Z. Liu, 37 A. Bunescu, T. M. Ha, Q. Wang and J. Zhu, Angew. Chem., Int. Adv. Synth. Catal., 2017, 359, 4278–4283. Ed., 2017, 56, 10555–10558. 24 Z. Liu, Z. Yang, X. Yu, H. Zhang, B. Yu, Y. Zhao and Z. Liu, 38 Y. Seki, K. Tanabe, D. Sasaki, Y. Sohma, K. Oisaki and Org. Lett., 2017, 19, 5228–5231. M. Kanai, Angew. Chem., Int. Ed., 2014, 53, 6501–6505. 25 J. Liu, J. Yang, W. Baumann, R. Jackstell and M. Beller, 39 F. C. Sequeira, B. W. Turnpenny and S. R. Chemler, Angew. Angew. Chem., Int. Ed., 2019, 58, 10683–10687. Chem., Int. Ed., 2010, 49, 6365–6368. 26 R. Sang, P. Kucmierczyk, R. Duehren, R. Razzaq, K. Dong, 40 K. Shen and Q. Wang, J. Am. Chem. Soc., 2017, 139, 13110– J. Liu, R. Franke, R. Jackstell and M. Beller, Angew. Chem., 13116. Int. Ed., 2019, 58, 14365–14373. 41 K. Shen and Q. Wang, Chem. Sci., 2015, 6, 4279–4283. 27 P. Ryabchuk, K. Stier, K. Junge, M. P. Checinski and 42 M. C. Paderes, L. Belding, B. Fanovic, T. Dudding, M. Beller, J. Am. Chem. Soc., 2019, 141, 16923–16929. J. B. Keister and S. R. Chemler, Chem.–Eur. J., 2012, 18, 28 L. Zhang, Y. Tang, Z. Han and K. Ding, Angew. Chem., Int. Ed., 1711–1726. 2019, 58, 4973–4977. 43 E. S. Sherman, P. H. Fuller, D. Kasi and S. R. Chemler, J. Org. 29 Y. Ge, Z. Han, Z. Wang and K. Ding, J. Am. Chem. Soc., 2019, Chem., 2007, 72, 3896–3905. –
Creative Commons Attribution 3.0 Unported Licence. 141, 8981 8988. 44 E. S. Sherman, S. R. Chemler, T. B. Tan and O. Gerlits, Org. 30 Z. Liu, Z. Yang, B. Yu, X. Yu, H. Zhang, Y. Zhao, P. Yang and Lett., 2004, 6, 1573–1575. Z. Liu, Org. Lett., 2018, 20, 5130–5134. 45 P. H. Fuller, J.-W. Kim and S. R. Chemler, J. Am. Chem. Soc., 31 J. P. Hallett and T. Welton, Chem. Rev., 2011, 111, 3508–3576. 2008, 130, 17638–17639. 32 A. M. Klibanov, Nature, 2001, 409, 241–246. 46 Y. B. Kang, X. M. Chen, C. Z. Yao and X. S. Ning, Chem. Commun., 2016, 52, 6193–6196. This article is licensed under a Open Access Article. Published on 21 February 2020. Downloaded 10/3/2021 12:09:27 AM.
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